A New Method for the Synthesis of 3-Substituted Indoles

Article abstract of DOI:10.1055/s-0035-1560210

Starting from readily accessible nitrones and electron-deficient acetylenes, a highly efficient and versatile synthetic protocol for 3-substituted indoles has been developed.

Full text of DOI:10.1055/s-0035-1560210

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2467–2471
letter
2467
R. Natarajan et al.
Letter
Synlett
A New Method for the Synthesis of 3-Substituted Indoles
Rakesh Natarajana
John P. Rappaib
Peruparampil A. Unnikrishnana
Sandhya Radhamani*c
Sreedharan Prathapan*a
B
O
B
A
Y(H)
O
O–
N+
O
O
H2C2O4-SiO2
Z
X
N
O
+
+
A
B
N
(Y)H
Y
X
Y(H)
A
H
X
Z
(Y)H
Z
10 examples
64–89% yield
a Department of Applied Chemistry, Cochin University of
Science and Technology, Kochi-682022, India
prathapans@gmail.com
b Department of Chemistry, Government Victoria College,
Palakkad-678001, India
c Department of Chemistry, N. S. S. College, Ottapalam,
Palakkad-679103, India
sandhyarunnithan@gmail.com
Received: 25.06.2015
Accepted after revision: 09.08.2015
Published online: 07.09.2015
pected, 4a underwent hydrolysis and in situ cyclization to
give phenyl(2-phenyl-1H-indol-3-yl)methanone (6a) in
quantitative yield. Though this method represents a simple
approach to indole synthesis,7 we surmised that a practical
alternative would be to hydrolyze 4a without separation
from the product mixture. In a repeat run, we treated ni-
trone 1a with acetylene 2a in acetonitrile. When all of the
starting materials were consumed, solvent was removed,
and the residue, redissolved in dichloromethane, was treat-
ed with oxalic acid adsorbed on silica gel. Hydrolysis of 4a
was completed in one hour, and the indole 6a generated
could be separated easily from other byproducts (such as
fluorenone and isoxazoline 5a) in higher yields vis-à-vis the
two-step method mentioned earlier. This result was quite
encouraging, and we adopted this as the general strategy
for subsequent reactions. Though triphenylnitrone 9 also
gave similar results, yield of the desired indole product was
higher with fluorenylidene nitrone 1a. So, we employed flu-
orenylidene nitrones for all optimization studies described
in this article. The more easily accessible aldonitrones fol-
low a different reaction course with electron-deficient acet-
ylenes and hence are not suitable precursors for indole syn-
thesis.5a,c
DOI: 10.1055/s-0035-1560210; Art ID: st-2015-d0473-l
Abstract Starting from readily accessible nitrones and electron-defi-
cient acetylenes, a highly efficient and versatile synthetic protocol for 3-
substituted indoles has been developed.
Key words indoles, nitrones, electron-deficient acetylenes, nucleo-
philic addition, 1,3-dipolar additions
Indole derivatives are valued for their wide range of ap-
plications.1 Ever since the pioneering synthesis by Fischer,2
indoles have remained attractive synthetic targets. Numer-
ous methods are reported for the synthesis of indoles and
several excellent reviews summarize synthesis protocols
developed for indoles.3,4 In a recent review, Taber assembled
strategies for indole synthesis into nine groups.3p We now
report a simple, highly versatile, and mechanistically ap-
pealing one-pot synthesis of 3-substituted indoles that can
be fitted into the type 5 indole synthesis formulated by
Taber.3p
While examining the mechanism of 1,3-dipolar addi-
tions, we observed the formation of unusual 1:1 adduct 4a
arising through an aza-Cope rearrangement in the reaction
between N-(9H-fluoren-9-ylidene)aniline oxide 1a and
phenylbenzoylacetylene (2a, Scheme 1).5,6 Acid-catalyzed
hydrolysis of imine 4a followed by in situ cyclization via an
intramolecular amine–carbonyl condensation reaction of
intermediate 8a should give 3H-indole 7a that will subse-
quently rearrange to 3-substituted indole 6a (Scheme 1). In
a preliminary experiment, we treated nitrone 1a with 2a to
give 4a in good yield (64%) along with isoxazoline 5a in mi-
nor amounts (19%).5a,c From the reaction mixture, 4a was
isolated in pure form by usual chromatographic techniques.
On treatment with oxalic acid adsorbed on silica gel, as ex-
Close examination of the indole product 6 reveals that it
retains most of the atoms present in the N-aryl substituent
and acetylene used. Substitution pattern of putative indole
products is dependent on substrate structure and hence is
easily predicted. This points towards the potential of our
method of indole synthesis to selectively synthesize indoles
having desired substituents at the 2-, 3-, 4-, 5-, 6-, and 7-
positions. Such flexibility makes indole synthesis reported
here unique and potentially useful.
In order to establish generality and wide applicability of
this novel indole synthesis, we repeated the reaction of 1a
with electron-deficient acetylenes 2b–e (Figure 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2467–2471

2468
R. Natarajan et al.
Letter
Synlett
O
Ph
Ph
•
Ph
Ph
O–
N+
O
N+
COPh
MeCN
O
Ph
O
+
+
N
O
Ph
N
reflux, 4 h
Ph
O–
1a
2a
5a
4a
3
H2C2O4-SiO2
CH2Cl2, r.t.
Ph
O
Ph
Ph
O
O–
N+
O
Ph
Ph
Ph
O
N
N
NH2
8a
H
9
6a
7a
Scheme 1 Reaction between nitrone 1a and acetylene 2a
COCH
COMe
CO2Me
CO2Me
CH
Ph
be explained on the basis of intramolecular nucleophilic
substitution reaction at the ester carbonyl with the amino
group as nucleophile and the methoxy group as the nucleo-
fuge. On the other hand, in the reaction between nitrone 1a
and acetylenes 2b,d, indoles 6b,d were exclusively generat-
ed in high yields (Scheme 2). The cyclization step is highly
selective, and the other possible isomer was not formed in
detectable amounts in any of those reactions. In the case of
acetylenes 2a–c the corresponding isoxazoline byproducts
5a–c were formed in minor amounts. In the case of acety-
lenes 2d,e, the corresponding indoles and fluorenone were
the only isolable products. Product distribution in the reac-
tion between nitrone 1a and acetylenes 2a–e is summa-
rized in Table 1.8 Best results are obtained with methyl
propiolate (2d).
Ph
Ph
H
Ph
2b
2c
2d
2e
Figure 1 Acetylenes used in indole synthesis
In all cases, the corresponding indole derivatives were
formed in good yields. With unsymmetrical intermediates
8b–e, two regioisomeric indole isomers could be generated.
The major product formed in such cases is easily predicted
on the basis of relative reactivity of the two carbonyl
groups. For example, in the reaction between nitrone 1a
and 4-phenylbut-3-yn-2-one (2c), (2-methyl-1H-indol-3-
yl)(phenyl)methanone (6c) was generated along with the
isoxazoline derivative and fluorenone. In this case, the
more reactive acetyl group undergoes condensation with
the amine functionality in preference to the less reactive
benzoyl group. Similarly, in the reaction between 1a and 2e,
6f was formed as the major product. Formation of 6f may
In order to extend the scope of indole synthesis, we ex-
amined the reaction of fluorenylidene nitrones having a
methyl substituent at different positons of the N-aryl group
with methyl propiolate (2d). Pattern revealing regioselec-
A
B
B
O
O
O
O
B
COB
A
A
B
A
O
O
N
N
N
NH2
H
A
H
Ph
5b,c
6b,d
8b–e
6c,f
2b–e
b A = Ph, B = styryl
c A = Ph, B = Me
d A = H, B = OMe
e A = Ph, B = OMe
f A = Ph, B = OH
Scheme 2 Indoles formed in the reaction between 1a and 2b–e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2467–2471

2469
R. Natarajan et al.
Letter
Synlett
Table 1 Product Distribution in the Reaction between Nitrone 1a and
Acetylenes 2a–e8
CO2Me
CO2Me
1. MeCN, reflux, 4 h
O–
N+
+
Entry
Nitrone
Acetylene
Indole (%)
Isoxazoline (%)
N
H
2. H2C2O4-SiO2, r.t.
H
1
2
3
4
5
1a
1a
1a
1a
1a
2a
2b
2c
2d
2e
6a (64)9a
6b (67)9b
6c (66)9c
6d (84)9d–g
6f (82)9h
5a (19)5a,c
5b (16)10
18
2d
19 (89%)
5c (18)10
Scheme 4 Reaction between nitrone 18 and acetylene 2d
–
–
Yet another advantage of this method is that the fluore-
none, generated as a byproduct in the indole-forming step,
can subsequently be recycled for the generation of a fresh
batch of fluorenylidene nitrone that can then be converted
into indole. As stated earlier, most atoms present in the
acetylene and N-aryl substituent are retained in the indole
product. Based on these, we complete the reaction cacle for
a flexible yet highly atom-efficient synthesis of 1H-indoles
(Scheme 5). Common methods for indole synthesis3,4,9 fail
to meet the simplicity and atom efficiency achieved by this
approach.
Efficient methods are available for the synthesis of ni-
trones,12 and several electron-deficient acetylenes are easi-
ly accessible. Oxalic acid adsorbed on silica gel is one of the
cheapest, safest, and most easily handled acid catalysts. Ex-
pensive catalysts are not required, and the reaction condi-
tions are mild. More importantly, the method is flexible
enough to introduce a desired group at a predetermined po-
sition. These advantages make our indole synthesis unique
for its efficiency, flexibility, wide applicability, and mecha-
nistic appeal. Shortcomings of the strategy include the fact
that indoles generated will, by default, have an electron-
withdrawing substituent at the 3-position, it is not possible
tivity in the indole formation reaction is presented in
Scheme 3. Nitrone 10, having a substituent at the 4-posi-
tion of the N-aryl ring, gave the corresponding 5-substitut-
ed indole 139d,e exclusively. Similarly, nitrone 11 with the
methyl substituent at the 2-position gave the correspond-
ing 7-substituted indole 14.9d,f On the other hand, nitrone
12, having methyl substituent at the 3 position of the N-aryl
ring, gave a mixture of 4- and 6-substituted indoles (159d
and 169g) in a 3:1 ratio. Regioselectivity in this case could be
explained on the basis of an unequal rotomer population of
intermediate 17 involved in the nitrone–acetylene reac-
tion.5c
The versatility of our method was further demonstrated
by near-quantitative generation of benzo[g]indole 199i,j in
the reaction between 2d and N-(9H-fluoren-9-
ylidene)naphthalen-1-amine oxide (18)5a (Scheme 4). Ben-
zo[g]indole derivatives are important for their biological ac-
tivity and potential application as fluorescent probes.11 Our
method provides easy access to benzo[g]indole 19 in high
yields.
O–
N+
O–
N+
O–
N+
12
10
11
2d
N
O
2d
2d
•
O
CO2Me
CO2Me
CO2Me
+
OMe
CO2Me
17
N
N
N
N
H
H
H
H
13 (84%)
14 (82%)
15 (63%)
16 (21%)
Scheme 3 Regioselectivity in nitrone–acetylene reactions; arrows point to potential sites for aza-Cope rearrangement in intermediates analogous to
175a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2467–2471

2470
R. Natarajan et al.
Letter
Synlett
O
B
O–
N+
NH2
MCPBA
N
X
A
X
X
A
A
O
H2N
H2C2O4
O
O
O
O
+
N
B
B
X
X
(A)B
O
A(B)
X
N
H
Scheme 5 Reaction cycle for indole formation
to introduce a substituent specifically at positions 4 and 6,
and, in some cases, it may not be possible to predict 2- and
3-substituents.
2010, 110, 4489. (k) Maes, B. U. W. Heterocyclic Scaffolds II:
Reactions and Applications of Indoles, In Topics in Heterocyclic
Chemistry; Vol. 26; Gribble, G. W., Ed.; Springer: Berlin, 2010.
(l) Barden, T. C. Heterocyclic Scaffolds II: Reactions and Applica-
tions of Indoles, In Topics in Heterocyclic Chemistry; Vol. 26;
Gribble, G. W., Ed.; Springer: Berlin, 2010, 31. (m) Biswal, S.;
Sahoo, U.; Sethy, S.; Kumar, H. K. S.; Banerjee, M. Asian J. Pharm.
Clin. Res. 2012, 5, 1.
Acknowledgment
S.P. is indebted to Professor William C. Agosta for introducing him to
the field of nitrogen heterocycles. R.N. is thankful to CSIR for the
award of a Senior Research Fellowship. SR acknowledges UGC for fi-
nancial assistance in the form of a minor research grant (1622-
MRP/14-15/KLCA025/UGC-SWRO). DST (PURSE and FIST grants),
UGC-SAP, and Kerala Government provided additional financial sup-
port. SAIF (STIC) CUSAT provided spectral and analytical data. Sister
Jemini Jose is acknowledged for partial experimental assistance.
(2) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.
(3) For reviews on indole synthesis, see: (a) Robinson, B. Chem. Rev.
1969, 69, 227. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045. (c) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417.
(d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(f) Kruger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350,
2153. (g) Patil, S. A.; Patil, R.; Miller, D. D. Curr. Med. Chem. 2009,
16, 2531. (h) Russel, J. S.; Pelkey, E. T. Prog. Heterocycl. Chem.
2009, 20, 122. (i) Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem.
Asian J. 2009, 4, 1036. (j) Candeias, N. R.; Branco, L. C.; Gois, P. M.
P.; Afonso, C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109, 2703.
(k) Palmisano, G.; Penoni, A.; Sisti, M.; Tibiletti, F.; Tollari, S.;
Nicholas, K. M. Curr. Org. Chem. 2010, 14, 2409. (l) Song, J. J.;
Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N. K.; Senanayake, C. H.
ARKIVOC 2010, (i), 390. (m) Cacchi, S.; Fabrizi, G.; Goggiamani,
A. Org. Biomol. Chem. 2011, 9, 641. (n) Vicente, R. Org. Biomol.
Chem. 2011, 9, 6469. (o) Patil, S. A.; Patil, R.; Miller, D. D. Curr.
Med. Chem. 2011, 18, 615. (p) Taber, D. F.; Tirunaharai, P. V. Tet-
rahedron 2011, 67, 7195. (q) Platon, M.; Amardeil, R.;
Djakovitch, L.; Hierso, J. C. Chem. Soc. Rev. 2012, 41, 3929.
(r) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012,
41, 7247. (s) Shiri, M. Chem. Rev. 2012, 112, 3508. (t) Gataullin,
R. R. Russ. J. Org. Chem. 2013, 49, 151. (u) Inman, M.; Moody, C. J.
Chem. Sci. 2013, 4, 29. (v) Melander, R. J.; Minvielle, M. J.;
Melander, C. Tetrahedron 2014, 70, 6363.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560210.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Sugden, J. K.; Yoloye, T. O. Pharm. Acta Helv.
1978, 53, 65. (c) Sundberg, R. J. Indoles; Academic Press:
London, 1996. (d) Rahman, A.; Basha, A. Indole Alkaloids;
Harwood Academic: Amsterdam, 1998, 141. (e) Gupta, R. R.
Heterocyclic Chemistry; Vol. 2; Springer: New York, 1999, 193.
(f) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (g) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278.
(h) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.
(i) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2007, 24, 843.
(j) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2467–2471

2471
R. Natarajan et al.
Letter
Synlett
(4) For some recent reports on indole synthesis, see: (a) Newman,
S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416. (b) Cacchi,
S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile,
P. Org. Lett. 2010, 12, 3279. (c) Levesque, P.; Forunier, P.-A. J.
Org. Chem. 2010, 75, 7033. (d) He, Z.; Li, H.; Li, Z. J. Org. Chem.
2010, 75, 4296. (e) McAusland, D.; Seo, S.; Pintori, D. G.;
Finlayson, J.; Greaney, M. F. Org. Lett. 2011, 13, 3667.
(f) Kothandaraman, P.; Mothe, S. R.; Toh, S. S. M.; Chan, P. W. H.
J. Org. Chem. 2011, 76, 7633. (g) Bonnamour, J.; Bolm, C. Org.
Lett. 2011, 13, 2012. (h) Kim, J. H.; Lee, S.-G. Org. Lett. 2011, 13,
1350. (i) Yan, Q.; Luo, J.; Zhang-Negrerie, D.; Li, H.; Qi, X.; Zhao,
K. J. Org. Chem. 2011, 76, 8690. (j) Zhao, Y.; Li, D.; Zhao, L.;
Zhang, J. Synthesis 2011, 873. (k) Ali, M. A.; Punniyamurthy, T.
Synlett 2011, 623. (l) Yoshida, K.; Hayashi, K.; Yanagisawa, A.
Org. Lett. 2011, 13, 4762. (m) Zhang, Z.-G.; Haag, B. A.; Li, J.-S.;
Knochel, P. Synthesis 2011, 23. (n) Varela-Fernández, A.; Varela,
J. A.; Saá, C. Synthesis 2012, 44, 3285. (o) Wei, Y.; Deb, I.;
Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098. (p) Gore, S.;
Baskaran, S.; König, B. Org. Lett. 2012, 14, 4568. (q) Porcheddu,
A.; Mura, M. G.; De Luca, L.; Pizzetti, M.; Taddei, M. Org. Lett.
2012, 14, 6112. (r) Jadhav, J.; Gaikwad, V.; Kurane, R.; Salunkhe,
R.; Rashinkar, G. Synlett 2012, 23, 2511. (s) Selander, N.;
Worrell, B. T.; Chuprakov, S.; Velaparthi, S.; Fokin, V. V. J. Am.
Chem. Soc. 2012, 134, 14670. (t) Nanjo, T.; Tsukano, C.;
Takemoto, Y. Org. Lett. 2012, 14, 4270. (u) Lu, B. Z.; Wei, H.-X.;
Zhang, Y.; Zhao, W.; Dufour, M.; Li, G.; Farina, V.; Senanayake, C.
H. J. Org. Chem. 2013, 78, 4558. (v) Reddy, B. V. S.; Reddy, M. R.;
Rao, Y. G.; Yadav, J. S.; Srighar, B. Org. Lett. 2013, 15, 464.
(w) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett. 2013, 15,
1802. (x) Lin, A.; Yang, J.; Hashim, M. Org. Lett. 2013, 15, 1950.
(y) Ji, X.; Huang, H.; Wu, W.; Jiang, H. J. Org. Chem. 2013, 78,
11155.
(5) (a) Radhamani, S.; Natarajan, R.; Unnikrishnan, P. A.; Prathapan,
S.; Rappai, J. P. New J. Chem. 2015, 39, 5580. (b) John, P. R. PhD
Thesis; Cochin University of Science and Technology: Cochin,
India, 2010. (c) Sandhya, R. PhD Thesis; Cochin University of
Science and Technology: Cochin, India, 2014.
(6) For a similar cyclization reaction, see: Pecak, W. H.; Son, J.;
Burnstine, A. J.; Anderson, L. L. Org. Lett. 2014, 16, 3440.
(7) For earlier reports on nitrone to indole conversions, see:
(a) Reaction of N-arylnitrone and ketenimine: Tsuge, O.;
Watanabe, H.; Masuda, K.; Yousif, M. M. J. Org. Chem. 1979, 44,
4543. (b) Reaction of nitrones with (phenylsulfonyl)alkynes:
Parpani, P.; Zecchi, G. J. Org. Chem. 1987, 52, 1417. (c) Reaction
of α,β-unsaturated N-arylnitrones with acetylenes: Huehls, C.
B.; Hood, T. S.; Yang, J. Angew. Chem. Int. Ed. 2012, 51, 5110.
(8) General Procedure
(9) For additional references on 3-substituted indoles, see:
(a) Nanjo, T.; Yamamoto, S.; Tsukano, C.; Takemoto, Y. Org. Lett.
2013, 15, 3754. (b) Black, D. S.; Debdas, R. B.; Kumar, N. Aust. J.
Chem. 1992, 45, 611. (c) Coffman, K. C.; Palazzo, T. A.; Hartely, T.
P.; Fettinger, J. C.; Tantillo, D. J.; Kurth, M. J. Org. Lett. 2013, 15,
2062. (d) Hopkins, C. R.; Czekaj, M.; Kaye, S. S.; Gao, Z.; Pribish,
J.; Pauls, H.; Liang, G.; Sides, K.; Cramer, D.; Cairns, J.; Luo, Y.;
Lim, H.-K.; Vaz, R.; Rebello, S.; Maignan, S.; Dupuy, A.; Mathieue,
M.; Levella, J. Bioorg. Med. Chem. Lett. 2005, 15, 2734.
(e) Yamazaki, K.; Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68,
6011. (f) Ji, X.; Huang, H.; Wu, W.; Li, X.; Jiang, H. J. Org. Chem.
2013, 78, 11155. (g) Hirano, S.; Akai, R.; Shinoda, Y.; Nakatsuka,
S. Heterocycles 1995, 41, 255. (h) Mongel, A.; Palopl, J.; Ramirez,
C.; Font, M.; Fernandez, A. E. Eur. J. Med. Chem. 1991, 26, 179.
(i) Mitchell, G.; Rees, C. W. J. Chem. Soc., Chem. Commun. 1986,
399. (j) Mitchell, G.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1
1987, 413.
(10) Characterization Data for 5b and 5c
(E)-1-{2′,5′-Diphenyl-2′H-spiro[fluorene-9,3′-isoxazole]-4′-
yl}-3-phenylprop-2-en-1-one (5b)
Yellow solid, yield 16%; mp 105 °C. IR (KBr): νmax = 3058 (=CH
stretch), 1649 (C=O stretch) cm–1. 1HNMR (400 MHz, CDCl3): δ =
7.89–7.86 (m, 2 H), 7.67 (d, J = 7.6 Hz, 2 H), 7.64–7.60 (m, 1 H),
7.57–7.53 (m, 4 H), 7.36–7.32 (m, 2 H), 7.27–7.16 (m, 6 H),
6.99–6.91 (m, 4 H), 6.81–6.76 (m, 1 H), 6.61–6.58 (m, 2 H), 6.36
(d, J = 15.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 183.9, 163.1,
145.9, 144.9, 140.8, 140.7, 134.9,131.7, 130.2, 129.8, 129.4,
128.8, 128.6, 128.1, 128.0, 127.9, 127.0, 125.4, 124.7, 123.6,
120.1, 118.3, 117.0, 84.9. MS: m/z = 503 [M+]. Anal. Calcd for
C
36H25NO2: C, 85.86; H, 5.00, N, 2.78. Found: C, 85.82; H, 4.98; N,
2.75.
1-{2′,5′-Diphenyl-2′H-spiro[fluorene-9,3′-isoxazole]-4′-
yl}ethanone (5c)
Yellow solid, yield 18%, mp 124 °C. IR (KBr): νmax = 3058 (=CH
stretch), 1649 (C=O stretch) cm–1. 1HNMR (400 MHz, CDCl3): δ =
7.84–7.81 (m, 2 H), 7.65–7.52 (m, 6 H), 7.37–7.33 (m, 2 H),
7.26–7.22 (m, 3 H), 6.93–6.89 (m, 2 H), 6.79–6.75 (m, 1 H),
6.56–6.53 (m, 2 H), 2.28 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
192.4, 163.4, 145.9, 144.9, 140.6, 131.4, 129.7, 129.4, 128.6,
128.3, 128.0, 127.9, 125.5, 123.6, 120.2, 117.3, 117.1, 84.5, 28.7.
MS: m/z = 415 [M+]. Anal. Calcd for C29H21NO2: C, 83.83; H, 5.09;
N, 3.37. Found: C, 83.78; H, 5.05; N, 3.35.
(11) (a) Boger, D. L.; Desharnais, J.; Capps, K. Angew. Chem. Int. Ed.
2003, 42, 4138. (b) Tietze, L. F.; Schuster, H. J.; Schmuck, K.;
Schuberth, I.; Alves, F. Bioorg. Med. Chem. 2008, 16, 6312.
(c) Helsley, G. C.; Effland, R. C.; Davies, L. US 3997557, 1976;
Chem. Abstr. 1977, 86, 139850 (d) Chen, J.; Burghart, A.;
Derecskei-Kovacs, A.; Burgess, K. J. Org. Chem. 2000, 65, 2900.
(12) For nitrone syntheses, see: (a) Johnson, A. W. J. Org. Chem. 1963,
28, 252. (b) Mugnier, Y.; Gard, J.-C.; Huang, Y.; Couture, Y.; Lasia,
A.; Lessarc, J. J. Org. Chem. 1993, 58, 5329. (c) Abou-Gharbia, M.;
Joullie, M. M. Synthesis 1977, 5, 318. (d) Magid, A.; Abou-Ghar-
bia, M. A.; Joulli, M. M. J. Org. Chem. 1979, 44, 2961. (e) Breuer,
E.; Aurich, H. G.; Nielsen, A. In Nitrones and Nitronic Acid Deriva-
tives: An Update in Nitrones, Nitronates and Nitroxides; John
Wiley and Sons: Chichester, 1989. (f) Feuer, H. In Nitrile Oxides,
Nitrones and Nitronates in Organic Synthesis: Novel Strategies in
Synthesis, 2nd ed.; John Wiley and Sons: Chichester, 2008.
A 1:1 mixture (1 mmol each) of nitrone and acetylene in MeCN
(10 mL) was stirred under reflux for 4 h. After complete con-
sumption of starting materials, solvent was evaporated off, and
the residue was redissolved in CH2Cl2 (10 mL) in the same flask.
Oxalic acid (1 mmol) adsorbed on silica gel (1 g) was added to
the same pot, and the mixture was stirred at r.t. for 1 h. After
completion of the reaction, the solvent was removed, and the
products were isolated by column chromatography over silica
gel using mixtures of hexane and EtOAc as eluents. In all reac-
tions, fluorenone was formed as a byproduct in yields compara-
ble to those cited for the indoles. Nitrones were prepared by
recycling the fluorenone.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2467–2471